The present invention is related to compounds that exhibit analgesic activity and in particular compounds exhibiting analgesia due to their opioid receptor affinity.
Many natural alkaloids and related analogs bind to specific opioid receptors and elicit an analgesic response similar to classic narcotic opiates. Many different types of opioid receptors have been shown to coexist in higher animals. For example, see W. Martin et al., J. Pharmacol. Exp. Ther 197, p. 517 (1975); and J. Lord et al., Nature (London), 257, p.495 (1977). Three different types of opioid receptors have been identified. The first, xcex4, shows a differentiating affinity for enkephalin-like peptides. The second, xcexc, shows enhanced selectivity for morphine and other polycyclic alkaloids. The third, xcexa, exhibits equal affinity for either group of the above ligands and preferential affinity for dynorphin. In general, the xcexc receptors seem to be more involved with analgesic effects. The xcex4 receptors appear to deal with behavioral effects, although the xcex4 and the xcexa receptors may also mediate analgesia.
Each opioid receptor, when coupled with an opiate, causes a specific biological response unique to that type of receptor. When an opiate activates more than one receptor, the biological response for each receptor is affected, thereby producing side effects. The less specific and selective an opiate may be, the greater the chance of causing increased side effects by the administration of the opiate.
Opiates can cause serious and potentially fatal side effects. Side effects such as respiratory depression, tolerance, physical dependence capacity, and precipitated withdrawal syndrome are caused by nonspecific interactions with central nervous system receptors. See K. Budd,
In International Encyclopedia of Pharmacology and Therapeutics; N. E. Williams and H. Wilkinson, Eds., Pergammon: (Oxford), 112, p.51 (1983). It is therefore an object of the present invention to provide compounds having analgesic effects but having as few side-effects as possible.
In one aspect, the present invention provides novel thio aminotetralin compounds represented by formula (I): 
and pharmaceutically acceptable derivatives thereof;
wherein;
Z is S, SO or SO2,
X is selected from anyone of
(i) a bond;
(ii) xe2x80x94CR7R8xe2x80x94 wherein R7 and R8 are independently selected from the group consisting of H, OH, halogen, CN, COOH, CONH2, amino, nitro, SH, C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N; and COORC wherein Rc is C1-6alkyl, C2-6alkenyl or C2-6alkynyl; R7 and R8 can also be connected to form C3-8 cycloalkyl, a C3-8 cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms;
R1 is selected from the group consisting of H, C1-12alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-12alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-12alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C6-12 aryl, C6-12 aralkyl, C6-12 aryloxy, C1-12 acyl, heteroaryl having from 6 to 12 atoms, and phosphoryl;
R2 and R3 are independently selected from the group consisting of C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C6-12 aryl, C6-12 aralkyl, heteroaryl having from 6 to 12 atoms, and H; or
R2 and R3 may together form a saturated heterocycle of from 3 to 8 atoms;
R4 and R5 are independently selected from the group consisting of C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, and H;
R4 and R5 can also be connected to form C3-8 cycloalkyl, a C3-8 cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms;
R6 is hydrogen, OH, C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, Oxe2x80x94C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, Oxe2x80x94C2-6alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, Oxe2x80x94C2-6alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, halogen, CN, COOH, CONH2, amino, nitro, or SH;
with the provisos that:
1) not both R4 and R5 are H; and
2) at least one of R2 and R3 is H or C1-6 alkyl.
The compounds of the present invention are useful in therapy, in particular as analgesics.
In another aspect, there is provided a method of treating pain in a mammal, comprising administering to said mammal an analgesic amount of a compound or composition of the invention.
Still another aspect of the invention is the use of a compound according to formula (I), for the manufacture of a medicament for the treatment of pain.
In another aspect, there is provided pharmaceutical compositions comprising compounds of the present invention and pharmaceutically acceptable carriers, diluents or adjuvants.
X is preferably xe2x80x94CR7R8xe2x80x94 wherein R7 and R8 are independently selected from the group consisting of OH, halogen, CN, COOH, CONH2, amino, nitro, SH, C1-6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, H, and COORc wherein Rc is C1-6alkyl; R7 and R8 can also be connected to form a C3-8 cycloalkyl.
X is more preferably xe2x80x94CR7R8xe2x80x94 wherein R7 and R8 are independently selected from the group consisting of C1-6 alkyl, and H.
X is most preferably xe2x80x94CH2xe2x80x94.
R1 is preferably selected from the group consisting of H, C1-12alkyl, C6-12 aryl, and C6-12 aralkyl.
R1 is more preferably selected from the group consisting of C1-6alkyl, C6-12 aryl, and C6-12 aralkyl.
R1 is most preferably C1-6 alkyl.
R1 can also be 
xe2x80x83wherein n is an integer between 1 to 5, Rx and Rx1 are independently H, C1-6alkyl, C2-6alkenyl or C2-6alkynyl. More preferably, n is 1 or 2 and Rx and Rx1 are C1-6alkyl. Most preferably, Rx and Rx1 are methyl or ethyl.
In an alternative embodiment, R1 is selected from the group consisting of CH3, xe2x80x94(CH2)nxe2x80x94CH3, and xe2x80x94(CH2)nxe2x80x94Oxe2x80x94CH3 wherein n is an integer selected between 1 and 5. In an alternative preferred embodiment R1 is C6-12 aryl or heteroaryl having from 6 to 12 atoms.
In a further preferred embodiment, R1 is selected from the group consisting of 
wherein A is selected from the group consisting of C1-6 alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Oxe2x80x94C1-6 alkyl, Oxe2x80x94C2-6alkenyl, Oxe2x80x94C2-6alkynyl, Sxe2x80x94C1-6 alkyl, Sxe2x80x94C2-6alkenyl, Sxe2x80x94C2-6alkynyl, Nxe2x80x94C1-6 alkyl, Nxe2x80x94C2-6alkenyl, Nxe2x80x94C2-6alkynyl, CF3, fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COORz wherein Rz is C1-6alkyl, C2-6alkenyl or C2-6alkynyl.
In an alternative embodiment, R1 is C6-12 aralkyl or heteroaryl having from 6 to 12 atoms.
More preferably, R1 is selected from the group consisting of 
wherein A is selected from the group consisting of C1-6 alkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Oxe2x80x94C1-6 alkyl, Oxe2x80x94C2-6alkenyl, Oxe2x80x94C2-6alkynyl, Sxe2x80x94C1-6 alkyl, Sxe2x80x94C2-6alkenyl, Sxe2x80x94C2-6alkynyl, Nxe2x80x94C1-6 alkyl, Nxe2x80x94C2-6alkenyl, Nxe2x80x94C2-6alkynyl, CF3, fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COORz wherein Rz is C1-6alkyl, C2-6alkenyl or C2-6alkynyl and Y is xe2x80x94(CH2)mxe2x80x94wherein m is an integer selected between 1 and 5.
R1 is preferably 
wherein A and Y are as defined above.
A is preferably selected from the group consisting of C1-6 alkyl, Oxe2x80x94C1-6 alkyl, Sxe2x80x94C1-6 alkyl, OH, nitro, amino, aminoamidino, amidino, guanido, COOH, and COORa wherein Ra is C1-6alkyl, C2-6alkenyl or C2-6alkynyl. A is more preferably selected from the group consisting of C1-6 alkyl, OH, nitro, amino, aminoamidino, amidino, guanido, and COOH. A is most preferably selected from the group consisting of amidino, guanido, and OH.
R2 and R3 are preferably H.
R4 and R5 are preferably C1-4 alkyl substituted by a hydroxyl.
R4 and R5 are preferably C1-4 alkyl.
In a further preferred embodiment, R4 and R5 are independently selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, and isobutyl.
R4 and R5 are preferably ethyl.
R4 and R5 are preferably methyl.
R6 can be substituted at any position on the aromatic ring. More preferably R6 is adjacent to the carbon bearing the OH. In an alternative embodiment, the present invention provides compounds of the formula (II) or (III) 
and pharmaceutically acceptable derivative;
wherein each of X, Z, R1, R2, R3, R4, R5, and R6 are defined above.
R6 is preferably, H, methyl, halogen or ORb wherein Rb is C1-6alkyl, C1-6alkenyl or C1-6alkynyl.
R6 is most preferably H.
The compounds of the present invention contains at least 2 chiral centers which are marked by an asterik (*) on the general formula (I). The compounds of formula (I) thus exist in the form of different geometric (i.e. trans and cis) and optical isomers (i.e. (+) or (xe2x88x92) enantiomers). When there is 2 chiral centers at the position marked by the asteriks, the compounds may therefore be in the form of cis isomers or trans isomers. Each cis or trans isomers also exists as a (+) and (xe2x88x92) enantiomer. All such isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
Preferably the compounds of the present invention are in the form of the trans isomers. More preferably the compounds of the present invention are present in the form of trans (+) and trans (xe2x88x92) enantiomers.
Preferred compounds of the invention include:Trans-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol
(compound #1);Cis-7-Amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol
(compound #2); Trans-7-Amino-8,8-diethyl-6-methylsulfanyl-5,6,7,8-dihydro-naphthalen-2-ol
(compound #3);Trans-7-Amino-8,8-dimethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (compound #4);
Trans-7-Amino-8,8-dimethyl-6-(pyridin-2-ylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #5);
Trans-7-Amino-8,8-dimethyl-6-(pyrimidin-2-ylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #6);
Trans-7-Amino-6-(3-amino-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #7);
Trans-7-Amino-8,8-dimethyl-6-(4-methylsulfanyl-phenylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #8);
Trans-7-Amino-6-benzenesulfonylmethylsulfanyl-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #9);
Trans-2-(3-Amino-4,4-diethyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-acetamide (Compound #10);
Trans-(3-Amino-4,4-diethyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanylmethyl)-phosphonic acid diethyl ester (Compound #11);
Trans-7-Amino-8,8-diethyl-6-(2-hydroxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #12);
Trans-7-Amino-6-(5-amino-2H-[1,2,4]triazol-3-ylsulfanyl)-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #13);
Trans-7-Amino-6-(2-amino-ethylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #14);
Trans-7-Amino-6-(5-amino-2H-[1,2,4]triazol-3-ylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #15);
Trans-7-Amino-8,8-dimethyl-6-propylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #16);
Trans-7-Amino-6-isopropylsulfanyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #17);
Trans-7-Amino-6-(2-hydroxy-ethylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #18);
Trans-2-(3-Amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-acetamide (Compound #19);
Trans-7-Dimethylamino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #20);
8,8-dimethyl-trans-7-methylamino-6methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #21);
Trans-7-Amino-8,8-diethyl-6-phenylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #22);
8,8-dimethyl-trans-6-phenylsulfanyl-7-propylamino-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #23);
Trans-7-Amino-6-(2-amino-phenylsulfanyl)-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #24;
Trans-7-Amino-8,8-dimethyl-6-(2,2,2-trifluoro-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol Compound #25);
Trans4-(3-Amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-butyric acid ethyl ester (Compound #26);
Trans-7-Amino-6-benzenesulfonylmethylsulfanyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #27);
Trans-7-Amino-8,8-dimethyl-6-(3-phenyl-allylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #28);
Trans-7-Amino-6-isobutylsulfanyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #29);
Trans-7-Amino-8,8-dimethyl-6-(2-phenoxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #30);
Trans-7-Amino-8,8-diethyl-6-(2-phenoxy-ethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #31);
(xe2x88x92)Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,66,7,8-tetrahydro-naphthalen-2-ol (Compound #32);
(+)Trans-7-amino-8,8-dimethyl-6-methylsulfanyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #33);Trans-7-amino-6-(4-bromo-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ol (Compound #34);
Trans-7-amino-8,8-dimethyl-6-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #35);Trans7-Amino-6-(4-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #36);Trans-7-amino-6-(4amino-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #37);Trans-7-amino-6-(3-hydroxy-phenylsulfanyl)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (Compound #38);Trans-3-(3-Amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionic acid ethyl ester (Compound #39);Trans-7-amino-8,8-dimethyl-6-phenethylsulfanyl-5,6,7,8-tetrahydronaphthalen-2-ol (Compound #40);Trans-2-(3-amino-6-hydroxy-4,4-dimethyl 1,2,3,4-tetrahydronaphthalen-2-ylsulfanyl)-propionamide (Compound #41);Trans-3-(3-amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionic acid (Compound #42);Trans-2-[3-(3-Amino-6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylsulfanyl)-propionylamino]-3-(4-hydroxy-phenyl)-propionamide (Compound #43); 3-trans-(2-ethoxycarbonyl-ethylsulfanyl)-1,1-diethyl-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl (Compound #44); 3-trans-(2-carboxy-ethylsulfanyl)-1,1-diethyl-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl (Compound #45);
and pharmaceutically acceptable derivatives thereof; wherein said compound is in the form of the (+) enantiomer, the (xe2x88x92) enantiomer and mixture of the (+) and (xe2x88x92) enantiomer including racemic mixture.
More preferably the compound of the present invention is selected from the group consisting of compound#1, compound#3, compound#4, compound#5, compound#9, compound#11, compound#15, compound#31, compound#32, compound#33, compound#36, compound#37, compound#39 compound#41, compound#43, compound#44 and compound #45.
Most preferably the compound of the present invention is selected from the group consisting of compound#1, compound#3, compound#5, compound#32, compound#33, compound#36, compound#44 and compound#45.
As used in the present application the term xe2x80x9cpainxe2x80x9d represents xe2x80x9can unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. The term xe2x80x9cpainxe2x80x9d also includes xe2x80x9cacute painxe2x80x9d and chronic pain.
Acute pain is usually immediate and of a short duration. Acute pain can be present further to an injury, short-term illness, or surgical/medical procedure.
Examples of acute pain include a burn, a fracture, an overused muscle, or pain after surgery. Cancer pain may be long-lasting but acute due to ongoing tissue damage.
Some chronic pain is due to damage or injury to nerve fibers themselves (neuropathic pain).
Chronic pain can result from diseases, such as shingles and diabetes, or from trauma, surgery or amputation (phantom pain). It can also occur without a known injury or disease.
The present invention s directed to the treatment of all type of pain, including acute and chronic pain.
As used in this application, the term xe2x80x9calkylxe2x80x9d represents an unsubstituted or substituted (by a halogen, nitro, aminoamidino, amidino, guanido, CONH2, COOH, Oxe2x80x94C1-6 alkyl, Oxe2x80x94C2-6 alkenyl, Oxe2x80x94C2-6 alkynyl, amino, hydroxyl or COOQ, wherein Q is C1-6 alkyl, C2-6 alkenyl, a C2-6 alkynyl) straight chain, branched chain, or cyclic hydrocarbon moiety (e.g. isopropyl, ethyl, flurohexyl or cyclopropyl). The term alkyl is also meant to include alkyls in which one or more hydrogen atoms is replaced by an halogen, more preferably, the halogen is fluoro (e.g., CF3xe2x80x94, or CF3CH2xe2x80x94).
The term xe2x80x9csaturated heterocyclexe2x80x9d represents a carbocyclic ring in which one or more of the from 3 to 8 atoms of the ring are elements other than carbon, such as N, S and O;
The term xe2x80x9carylxe2x80x9d represents an aromatic ring having from 6 to 12 carbon atoms, which may be substituted by a C1-6 alkyl, C2-6 alkenyl, a C2-6 alkynyl, halogen, nitro, aminoamidino, amidino, guanido, CONH2, COOH, Oxe2x80x94C1-6 alkyl, Oxe2x80x94C2-6 alkenyl, Oxe2x80x94C2-6 alkynyl, amino, hydroxyl or COOQ, wherein Q is C1-6 alkyl, C2-6 alkenyl, a C2-6 alkynyl, such as phenyl and naphthyl.
The term xe2x80x9caralkylxe2x80x9d represents an aryl group attached to the adjacent atom by a C1-6alkyl, C1-6alkenyl, or C1-6alkynyl(e.g., benzyl).
The term xe2x80x9caryloxyxe2x80x9d represents an aryl or aralkyl moiety covalently bonded through an oxygen atom (e.g., phenoxy).
The term xe2x80x9cheteroarylxe2x80x9d represents an aromatic ring in which one or more of the from 6 to 12 atoms in the ring are elements other than carbon, such as O, N, and S (e.g pyridine, isoquinoline, or benzothiophene).
The term xe2x80x9cacylxe2x80x9d refers to a radical derived from a carboxylic acid, substituted (by halogen(F, Cl, Br, I), C6-20 aryl or C1-6 alkyl) or unsubstituted, by replacement of the OH group. Like the acid to which it is related, an acyl radical may be aliphatic or aromatic, substituted (by halogen, C1-5 alkoxyalkyl, nitro or OH) or unsubstituted, and whatever the structure of the rest of the molecule may be, the properties of the functional group remain essentially the same (e.g., acetyl, propionyl, isobutanoyl, pivaloyl, hexanoyl, trifluoroacetyl, chloroacetyl, and cyclohexanoyl).
The term xe2x80x9cphosphorylxe2x80x9d represents a radical derived from a phosphono moeity in which the hydrogen atom of at least one of the xe2x80x94OH can be replaced by C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C6-12 aryl, C6-12 aralkyl, and C6-12 heteroaryl(e.g., diethoxyphosphorylmethyl).
The term xe2x80x9chalogenxe2x80x9d encompasses chloro, fluoro, bromo and iodo;
In the present application the following abbreviations are used:
When there is a sulfur atom present, the sulfur atom can be at different oxydation level, S, SO, or SO2. All such oxydation level are within the scope of the present invention.
In yet another aspect of the invention, there is provided a process for preparing compounds of formula (I). The process is described in scheme 1 wherein each of X, R1, R2, R3, R4, R5 and R6 are as defined above and P, P1, P2, and P3 are protecting groups. If desired, the sulfur of the compound of formula Ia can be oxydized to Sxe2x95x90O or SO2 by methods well known in the art. 
Step 1
The starting ketone AA was dissolved in a suitable solvent such as DMF, acetonitrile, THF, DME and was treated with sodium hydride or any other base such as potassium t-butoxide, sodium bis(trimethylsilyl)amide. The resulting mixture was then treated with ethyl iodide or any other alkyl halide such as methyl iodide, allyl bromide, diiodobutane to produce the compound A.
Step 2
The compound A was dissolved in a suitable solvent such as pyridine, DMF, ethanol and was treated with hydroxylamine hydrochloride or any other hydroxylamine salt such as hydroxylamine sulfate, hydroxylamine bromide to produce the compound B.
Step 3
The compound B was dissolved in a suitable solvent as THF, dioxane, DME, and was treated with LAH or any other reducing agent such as red-Al in presence of diethylamine or any other amine such as methylbutylamine, dipropylamine. The mixture was then heated to 50xc2x0 C. or at any higher temperature to produce the compound C.
Step 4
The compound C in was dissolved in a suitable solvent as dichloromethane (CH2Cl2) or in any other solvent such as dichloroethane, and was treated with BBr3 or any other demethylating agent such as BCl3, HBr, to produce the compound D.
Step 5
The amino or hydroxyl groups of the compound D were protected with Boc or with any other protecting group, to produce the compound E. Protective groups are described in Protective Groups in Organic Synthesis, 2nd ed., Greene and Wuts, John Wiley and Sons, New York, 1991 which is herein incorparated by reference.
Step 6
The compound E was dissolved in a suitable solvent such as ethanol or in any other alcohol such as methanol, propanol, butanol and was treated with pyridinium p-toluenesulfonate (PPTS) or any other acid or Lewis acid such as HCl, BF3.OEt 2, PTSA, to produce the compound F. Alternatively, a non alcoholic solvent can be used in combination with an appropriate amount of an alcohol and a suitable Lewis acid such as ytterbium triflate see for example Tetrahedron Letters, Vol. 37, No.43, pp7717-7720, 1996 which is herein incorparated by reference.
Step 7
The protecting groups of the compound F were removed under appropriate conditions e.g. with TFA or with any other acid such as HCl, PTSA, to produce the compound Ia.
It will be appreciated that certain substituents require protection during the course of the synthesis and subsequent deprotection. For example, it may be necessary to protect an hydroxyl group by converion to an alkoxy or an ester and subsequently deprotected. Protective groups for other substituents are described in Protective Groups in Organic Synthesis, 2nd ed., Greene and Wuts, John Wiley and Sons, New York, 1991.
In another aspect, there is provided a method of agonizing or activating opioid receptors in a mammal comprising administering to said mammal an opioid receptor agonizing or activating amount of a compound or composition of the invention.
There is also provided pharmaceutically acceptable compositions comprising compounds of the present invention and derivatives thereof, in combination with pharmaceutically acceptable carriers diluents or adjuvants.
By xe2x80x9cpharmaceutically acceptable derivativesxe2x80x9d is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of compounds of formula (I) or (II) or any other compound such as a prodrug which, upon administration to the recipient, is capable of providing (directly or indirectly) compounds of formula (I) or (II) or an active metabolite or residue thereof.
The present invention also provides pharmaceutical compositions which comprise a pharmaceutically effective amount of a compound of the invention, or pharmaceutically acceptable salts thereof, and preferably, a pharmaceutically acceptable carrier, diluent or adjuvant. The term xe2x80x9cpharmaceutically effective amountxe2x80x9d is the amount of compound required upon administration to a mammal in order to induce analgesia. Also, the term xe2x80x9copioid receptor agonizing amountxe2x80x9d refers to the amount of compound administered to a mammal necessary to bind and/or activate opioid receptors in vivo.
Therapeutic methods of this invention comprise the step of treating patients in a pharmaceutically acceptable manner with those compounds or compositions. Such compositions may be in the form of tablets, capsules, caplets, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. The unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients. For example, binding agents, such as acacia, gelatin, sorbitol, or polyvinylpyrolidone; fillers, such as lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate; disintegrants, such as starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered orally in the form of solutions which may contain coloring and/or flavoring agents. The compounds may also be administered sublingually in the form of tracheas or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form.
The solid oral compositions may be prepared by conventional methods of blending, filling, tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
Liquid oral preparations may be in the form of emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may or may not contain conventional additives. For example suspending agents, such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats; emulsifying agents, such as sorbitan monooleate or acaci; non-aqueous vehicles (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of glycerine, propylene glycol, ethylene glycol, and ethyl alcohol; preservatives, for instance methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, n-propyl parahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid; and, if desired, conventional flavoring or coloring agents.
The compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously. For parenteral administration, the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. For parenteral administration, fluid unit dosage forms may be prepared by utilizing the compound and a sterile vehicle, and, depending on the concentration employed, may be either suspended or dissolved in the vehicle. Once in solution, the compound may be injected and filter sterilized before filling a suitable vial or ampoule and subsequently sealing the carrier or storage package. Adjuvants, such as a local anesthetic, a preservative or a buffering agent, may be dissolved in the vehicle prior to use. Stability of the pharmaceutical composition may be enhanced by freezing the composition after filling the vial and removing the water under vacuum, (e.g., freeze drying the composition). Parenteral suspensions may be prepared in substantially the same manner, except that the compound should be suspended in the vehicle rather than being dissolved, and, further, sterilization is not achievable by filtration. The compound may be sterilized, however, by exposing it to ethylene oxide before suspending it in the sterile vehicle. A surfactant or wetting solution may be advantageously included in the composition to facilitate uniform distribution of the compound.
The pharmaceutical compositions of this invention comprise a pharmaceutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier. Typically, they contain from about 0.01% to about 99% by weight, preferably from about 10% to about 60% by weight, of a compound of this invention, depending on which method of administration is employed.
The compounds of the present invention can be administered in combination with one or more further therapeutic agents. Preferably, the one or more further therapeutic agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, narcotics, antidepressants, anticonvulsants, corticosteroid, tramadol, sumatriptan, and capsaicin.
Without limitations, NSAIDs include aspirin (Anacin, Bayer, Bufferin), ibuprofen (Motrin, Advil, Nuprin), naproxen sodium (Aleve) and ketoprofen (Orudis KT)
Without limitations, narcotics include drugs derived from opium (opiates), such as morphine and codeine, and synthetic narcotics (opioids), such as oxycodone, methadone and meperidine (Demerol).
Without limitations, antidepressants include amitriptyline (Elavil), trazodone (Desyrel) and imipramine (Tofranil) may be used with other analgesics. These drugs are especially useful for neuropathic, head and cancer pain.
Without limitations, anticonvulsants include drugs developed for epilepsy, these drugs, such as phonation (Dilantin) and carbamazepine (Tegretol), can also help control chronic nerve pain.
Tramadol (Ultram) is a synthetic analgesic used primarily for chronic pain, but is also prescribed for acute pain.
Sumatriptan (Imitrex), may reduce pain from migraine headache by constricting blood vessels.
Capsaicin (Zostrix), a topical cream made from an extract of red peppers, can help relieve skin sensitivity resulting from shingles. Capsaicin can also be used to treat pain from arthritis, cluster headaches, diabetic neuropathy and pain after mastectomy.
In another aspect of the invention, compounds may be used to identify opioid receptors from non-opioid receptors. For such use, compounds of the invention are radiolabeled e.g. by incorporating 3H or 14C within its structure or by conjugation to 125I. Such radiolabeled forms can be used directly to identify the presence of opioid receptors and in particular p opioid receptors in a receptor population. This can be achieved by incubating membrane preparations with a radiolabeled compound of the invention. The presence and or amount of opioid receptors in the preparation is determined from the difference in membrane-bound radioactivity against a control preparation devoid of opioid receptors. Furthermore, radiolabeled forms of the present compounds can be exploited to screen for more potent opioid ligands, by determining the ability of the test ligand-to displace the radiolabeled compound of the present invention.